Among persons with diabetes mellitus (DM), the complications of accelerated atherosclerosis remain the principal cause of death. The pathogenesis of the high incidence of cardiovascular disease, and worse prognosis, in patients with DM is poorly understood. BARI 2D is a multicenter randomized clinical trial investigating the affect of different approaches to treatment of coronary artery disease (revascularization vs. medical management) and to treatment of DM (insulin-providing vs. insulin-sensitizing) on long term outcomes among patients with DM. To date, few studies have examined the hypothesis that genetic variation may account for different responses to treatment and different outcomes for such patients. The PPAR gene pathway consists of interrelated genes that encode transcription factors, enzymes and downstream targets and coordinately act to regulate cellular processes central to glucose and lipid metabolism. With growing evidence that PPAR-related genes are associated with the development of insulin resistance, obesity, and DM, the PPAR gene pathway represents a key target for further investigation. Using a candidate gene approach, the PI has recently identified polymorphisms (SNPs) within the promoter of the PPARa gene that are significantly associated with 3-year mortality in patients with DM and acute coronary syndromes (ACS). Given the complex interrelationships between PPAR-pathway genes and gene products, as well as complex interactions with medications, investigation into genetic and pharmacogenetic associations with phenotypic markers and clinical outcome may be greatly enhanced if a more comprehensive gene pathway analysis is utilized. To accomplish this goal, we propose to utilize a targeted-genotyping 3K chip including SNPs from 223 PPAR-pathway genes: (Aim 1) To determine PPAR-pathway gene SNPs that show an association with clinical cardiovascular and diabetic outcomes among patients in BARI 2D; (Aim 2) To investigate putative mechanisms by examining potential associations between PPAR-pathway SNPs and prognostic atherosclerotic and diabetic phenotypic markers; (Aim 3) To examine PPAR-pathway genotype by randomized treatment interactions, including the pharmacogenetics of glucose control and genetic effects on the relative risk reduction by an initial strategy of revascularization vs. medical therapy; and (Aim 4) To investigate the "interactive-effect" between polymorphisms of PPAR-pathway genes using innovative statistical models. The proposed analysis should yield novel information about genetic associations between PPAR-pathway genes, phenotypic markers, and outcomes among patients with DM and cardiovascular disease and allow unique analyses probing significant genetic and pharmacogenetic interactions between these variants (genotypes and/or haplotypes) and multiple endpoints in BARI 2D The innovative approach described in this proposal has the potential to yield highly significant, new approaches to the treatment of patients with CAD and DM, specifically with respect to revascularization and pharmaceutical intervention. [unreadable] [unreadable] [unreadable]